LAUSR

In his prescient two-decade old editorial entitled “What only the embryo knows,” the late Stephen Jay Gould credits Karl Ernst von Baer for more than having discovered the mammalian egg in 1827. Besides publishing the first scholarly treatment of “modern” embryology in 1828, von Baer proposed that “The development of an organism is the history of growing individuality in every respect.” Gould goes on to paraphrase von Baer’s Law by stating “In other words, successive narrowing and determination of parts as complexity coagulates. No turning back after the blueprint becomes finalized from a broad mass of initial potential.” (The New York Times, on August 27, 2001). Occasionally, original research brings to the forefront an insight having much to do with an ongoing and seemingly intractable problem under study. With the hit parade of new papers using human embryos to gain insights into “our” developmental trajectory compared to the animal test models of yesteryear, the unexpected landmarks of early human development continue to surprise many in hot pursuit of the “perfect” conceptus. In the parlance of the day, those embryos bearing the complete signature of a pregnancy waiting to go to term. That said, we are in the throughs of a much-maligned debate whereby judgment calls at the heart of embryo selection are rendered based upon a wide range of behaviors and attitudes displayed by human conceptuses. Now that the ART field has had the opportunity to visualize the assorted behaviors of human embryos, the burden of proof has rested on embryologists in the modern sense to produce rhyme and reason of the remarkable cellular gymnastics on display from fertilization to hatched blastocysts. In the 20 years since Gould’s pronouncement above, the time seems appropriate to wander back down the ART alley way and reconsider underlying mechanisms that could form a tractable clinical platform upon which to improve outcomes from the “broad mass of initial potential.” Taking a step back in time to the first scientists to witness development of a mammalian embryo brings us to the pioneering work of Mulnard and his colleagues in Belgium who were the first to deploy time lapse microscopy of mouse embryos, defining in brilliant detail the process of compaction [1, 2]. Our earliest insights as to how the inner cell mass and trophectodermal lineages became determined was gleaned from later stages of this work in which patterns of cell division and positioning could be mapped for individual embryos with the precision and accuracy accorded embryologists—soon to be known as developmental biologists— of those halcyon times [3]. The intervening years between those primordial findings and our current evidence-based understanding of cleavage and most importantly compaction has transitioned along side breakthroughs in technology changing what we see and how we see it. For example, remodeling of the cell surface especially with respect to the advances being made in understanding how intercellular junctions led to the first level of complexity manifest as the sorting of inner cell mass and trophectoderm. Inherent to these seminal findings was the recognition of how the first embryonic epithelium formed and functioned by establishing polarity in a subset of blastomeres now appreciably better understood from a mechanistic point of view across many animal species [4, 5]. That the driving force, literally, would reside in the force-generating elements of the maternally inherited cytoskeleton has become clear [6]. Buttressed by two decades of research during which human embryos could be compared and contrasted to those of other mammalian forms, it remains fair to ask whether our knowledge base has offered insights into the question of why so few fertilized human eggs safely make the journey from zygote to blastocyst? Blastomere fragmentation as a behavior and cornerstone to the practice of embryo scoring, rests at the tipping point of making a fateful decision and wondering why such a behavior would be so commonplace among * David F. Albertini [email protected]